Isoflavones and many derivatives thereof possess a wide range of important biological properties including estrogenic effects. Isoflavanoids found in soy, such as genistein and daidzein, have also attracted interest as dietary phytoestrogens that might be effective for the treatment of hormone-dependent conditions and diseases. In examining the impact of the estrogenic activity of soy isoflavones (commonly referred to as phytoestrogens), one needs to consider not only the isoflavones and their conjugates that are ingested, but also biologically active metabolites that might be generated from them in vivo. Daidzein, an isoflavone in soy, can be converted to the corresponding chromane S-(−)equol, a compound with greater estrogenic activity than its precursor (See K. D. R. Setchell, N. M. Brown, E. Lydeking-Olsen. J. Nutrition, 2002, 132/12, pp 3577-3584). This reductive metabolic conversion is the result of the action of equol-producing gut microflora found in a proportion of the human population who are known as “equol producers”. Equol was first isolated from pregnant mare's urine in 1932 and was subsequently identified in the plasma of sheep (derived from formononetin found in red clover species). In 1982 it was first identified in human urine. Equol is a chiral center and therefore can exist in two enantiomeric forms. It has been recently established that S-(−)equol is the enantiomer produced by the metabolic reduction of isoflavones ingested by humans (see Setchell K D R, Clerici C, Lephart E D, Cole S J, Heenan C, Castellani D, Wolfe B, Nechemias L-Z, Brown N, Baraldi G, Lund T D, Handa R J, Heubi J E. S-Equol, a potent ligand for estrogen receptor-beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by intestinal bacterial flora. American Journal of Clinical Nutrition 2005; 81:1072-1079.
A convenient preparation of racemic (±) equol (7-hydroxy-3-(4′-hydroxyphenyl)-chroman) based on transfer hydrogenation of daidzein was published (K. Wahala, J. K. Koskimies, M. Mesilaakso, A. K. Salakka, T. K. Leino, H. Adlercreutz. J. Org. Chem., 1997, v 62, p 7690-7693), and more recently by J. A. Katzenellenbogen et al. (Bioorganic & Medicinal Chem., 2004, 12, pp 1559-1567). A procedure is known for isolation of enantiomeric S- and R-equol from the racemic mixture by chiral chromatographic resolution of (±) equol using a β-cyclodextrin column (see PCT Publication WO03/23056, published Jan. 29, 2004, and incorporated herein by reference). However, this approach has certain production rate limitations, and may not be suitable for making commercial quantities of enantioselective equol.
Therefore, a need remains to develop a cost-effective method of synthesizing commercial quantities of enantioselective equol and related enantioselective chromanes.